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Drug release using Electrospun Fibers

Electrospun nanofibers have been shown to be suitable for adhesion and proliferation of numerous cell types. To enhance its influence over cell response or to introduce pharmacological effects, drugs and other biomolecules have been incorporated to the nanofibers. The preferred drug release characteristic depends on the intended application. However, it is good to understand the stages which loaded drugs are being released into the medium. Drug releasing into the medium is primarily based on diffusion. For this to occur, the medium needs to penetrate into the polymer matrix to cause the diffusion of the drug to the exterior. The greater the distance between the drug molecule and the surface of the fiber, the longer is the diffusion duration. The diffusion distance from the core to the surface of the fiber may be affected by the cross-sectional profile of the fiber. Electrospun fibers are known to exhibit different fiber shape and profiles such as rounded, flat/ribbon or pitted. A flat fiber will have a shorter distance from the center to the surface along its width compared to a round fiber. Yu et al (2014) found that the drug release from electrospun Eudragit L100 flat fiber was found to be faster than that from a round fiber using the same material. Where sustained release of drug is preferred, conditions for electrospinning should be optimized to produce round fibers. Any barrier and strong adhesion between the drug molecules and the fiber matrix will also lengthen the diffusion duration. Polymer matrix which is easily penetrated by the medium will hasten the diffusion process. Similarly, polymer matrix which easily dissolves or degrade in the medium will also quickly release its contents. To control the rate of drug release is to control the above mentioned conditions.


Blending

Blending is probably the simplest and most straightforward method of incorporating drugs into electrospun fibers. The process involves either dissolving or dispersing the drug into the solution to be electrospun. The solution with the loaded drug is then electrospun to form fibers. If the drug is insoluble in the polymer solution, an alternative is to dissolve the drug in its solvent and mix it with the polymer solution. However, the amount of drug that can be loaded will be very much reduced. Ultra-sonication may also be used to uniformly dispersed drug particles into the polymer solution but the uniformity of the particle dispersion within the fibers following electrospinning needs to be verified. In some cases, a mixture of three or more substances is needed to form a homogeneous solution. Fu et al (2016) prepared a homogeneous solution comprising of polylactic acid (PLA), amorphous calcium phosphate (ACP), bovine serum albumin (BSA) and lecithin. BSA is water soluble but not in the solvent for dissolving PLA. Without ACP, a solution mixture comprising of lecithin, BSA, water and the solvent mixture (chloroform and N, N-dimethylformamide) were unstable and stratification appears after some time. With the resulting containing PLA/ACP/BSA/lecithin, Fu et al (2016) was able to successfully electrospin nanofibers. For some materials or processes, the need for post-electrospinning washing steps or treatment may be undesirable for drugs blended into the electrospun fibers as it may result in leaching of the drugs during the washing process or deactivating the drugs during post-electrospinning treatments. Therefore, where blending is used, it is important to consider the processes required to form the final product. This has been demonstrated by Losi et al (2020) in their preparation of fibrin fibers loaded with platelet lysate (PL). To avoid the need for washing fibrin polymerized electrospun fibrinogen/carrier polymer fibers, they electrospin fibrinogen fibers loaded with active compounds and fibrin polymerization was carried out by spraying thrombin onto the fibrinogen fibers and incubated for 30 min at 37 °C. The resultant drug loaded fibrin scaffold can be used without any further washing steps.

Blended system is usually associated with an initial burst released followed by sustained release over the next few days and weeks [Pillay et al 2013, Kim et al 2004]. However, there are reports of blended systems where the initial burst release is absent [Pillay et al 2013]. This may be due to the distribution of the drugs within the nanofibers as a result of electrical influences or drug-solvent interaction. There are a few reports of electrospun fibers where incorporation of water soluble drugs into hydrophobic polymer matrix showed an absence of initial burst releases [Verreck et al 2003, Zhao et al 2014]. Zhao et al 2014 hypothesized that the absence of initial burst release in their blended system of hydrophilic l-ascorbic acid 2-phosphate magnesium (Vit C) from electrospun polycaprolactone (PCL) scaffold is due to the migration of the hydrophilic component towards the core. They used two solvents in the preparation of the solution, dichloromethane (DCM) and N,N dimethyl formamide (DMF) or methanol. During electrospinning, the more volatile DCM will form a skin comprising mainly of PCL while Vit C is pushed towards the core. Due to the presence of hydrophobic PCL, a slow and sustained release of Vit C is observed.

An important function of having drugs encapsulated in electrospun fiber matrix is that the matrix protects the drugs from environmental degradation. Mira et al (2017) showed that electrospun poly(methyl vinyl ether-alt-maleic ethyl monoester) (PMVE-MA-ES) was ideal for encapsulation and release of 5-aminolevulinic acid (5-ALA). 5-ALA degrades quickly with a half-life at physiological pH and 50 °C of about 3 h. Therefore, the release vehicle must be able to unload the drugs quickly. In electrospun PMVE-MA-ES nanofibers, it is able to achieve 100% release of 5-ALA after 3 h. Encapsulated 5-ALA was able to maintain stability and biological activity for at least 3 months under storage.

Blending drugs into polymer solution and electrospinning to form fibers has been shown to facilitate complete drug release as it transforms crystalline state into amorphous state. Szabo et al (2021) compared the dispersion of amorphous solid dispersions (ASDs) made up of poorly soluble spironolactone (SPIR) and poly(vinylpyrrolidone-co-vinyl acetate) using spray drying and electrospinning. Both processes require the use of solvents for the dissolution of the active compounds. The release of spironolactone was carried in 0.1 N HCl dissolution media at a temperature of 37 °C. Both electrospun and spray dried samples dissolved quickly. Electrospun samples released more than 90% of its load in 20 min while the amount of SPIR released by spray dried samples plateaus at about 60%. The total amount of SPIR released by spray dried samples was the same as micronized crystalline SPIR. SPIR encapsulated using electrospinning and spray drying showed an amorphous state. However, spray dried SPIR contains 5 to 7 % crystalline nuclei which could have induced quick crystallization upon contact with media while electrospun samples contained less than 1% crystalline nuclei. Additional tests showed that slow evaporation rate of the solution such as in solvent casting method leads to greater crystallinity and hence lower dissolution of SPIR in the media. Electrospinning is also known for its fast solvent vaporisation rate and this may have contributed to its lower count of crystalline nuclei. Another factor would be the electric field effect that helps to maintain dispersion of SPIR. Electrospraying of SPIR solution was also found to yield better dissolution compared to spray dried samples which showed that electric field may have played a part.

Drugs loaded in electrospun carrier polymers may be amorphous immediately after the fibers have been collected. However, storage over a period of time may lead to re-crystallization of the drugs. Uhljar et al (2022) did a comparison of the ciprofloxacin (CIP)-loaded polyvinylpyrrolidone (PVP) electrospun fibers using a drum surface electrospinning setup and single nozzle electrospinning setup. At the same concentration, the single nozzle electrospun fibers have an average diameter of 323 nm while the drum surface electrospun fibers have an average diameter of 1167 nm. Comparing the crystallinity of the CIP in the fibers over a period of time up to 26 months, it was shown that the CIP-loaded PVP fibers from single nozzle electrospinning showed re-crystallization at the 8th month. However, for the CIP-loaded PVP fibers from the drum surface electrospinning setup, the CIP remained amorphous at 26 months. Given that PVP is water soluble and that PVP fibers from the drum surface electrospinning have a much larger diameter than the fibers from single nozzle electrospinning, it is likely that there is less influence of room-condition humidity on fibers with larger diameter. The increase in the crystallinity of CIP in the fibers invariably reduces the release rate of CIP.

Melt electrospinning may also be used for drug release. Since a high temperature is needed to melt the polymer for electrospinning, it is essential that the additives will not degrade at the melting temperature of the polymer. Lian and Meng (2017) demonstrated the potential use of PCL melt electrospun fibers for delivery of daunorubicin hydrochloride (DHCl), an antitumor drug. PCL has a relatively low melting point and a temperature of 90 °C is sufficient to melt the polymer for electrospinning. The drug loaded PCL was prepared by heating and melting the polymer and mixing the drug (10 wt%) into the molten polymer. The mixture was maintained at molten state for electrospinning. The resultant release characteristic of the drug loaded PCL electrospun fibers showed no initial burst release in PBS solution which is common in solution based drug loaded electrospun fibers. The absence of initial burst release was attributed to the hydrophobic nature of PCL which restrict water penetration. However, a faster release rate was observed after day 3 and this may be due to water penetration and diffusion into the fiber matrix. The drug release rate in the whole is still relatively slow with only 20% of the drugs released after 2 weeks. With the loaded drug significant inhibition of HeLa and glioma cells (U87) in vitro were observed.

In a blended system, having more drugs loaded into the matrix may not stretch the duration of drug release. Huo et al (2015) tested the release profile of water soluble Timosaponin B-II (TB-II) loaded in PLLA nanofibers at concentration of 10 wt%, 12 wt% and 15 wt%. All three concentrations showed an initial burst release of 30% to 40% of the drugs within the first 6 hours. The release slowed down significantly thereafter and after 21 days where about 70% to 80% of the drugs were released. Their study showed that nanofibers with higher concentration of drug loading were releasing greater percentage of drugs although their average diameters are about 220 to 230 nm. The increased release rate from higher drug loaded nanofibers may be due to the corresponding reduction in the matrix material. This may also lead to faster breakdown of the matrix material as greater volume of the drugs is being leached out.


In vitro cumulative percentage of TB-II released from the nanofibers at various time points (n = 3). [Huo et al. Journal of Nanomaterials, vol. 2015, Article ID 367964, 9 pages, 2015. This work is licensed under a Creative Commons Attribution 3.0 Unported License.]


Emulsion electrospinning

Most polymers used in electrospinning are soluble only in organic solvent. However, there are many drugs that exist in the form of salt that are soluble only in aqueous media. Emulsion electrospinning is designed to enable loading of these drugs into polymer dissolved organic solvent for spinning into fibers. Typical preparation of the solution for emulsion electrospinning is by dissolving the drug and polymer in aqueous and organic medium separately followed by mixing of the two solutions with an emulsifier. Vortexing is carried out to form the emulsion. The critical quality attributes identified for emulsion electrospinning are stability, viscosity and conductivity [Badawi et al 2014].


Core-shell


TEM image of core-shell nanofibers using co-axial electrospinning. [Qian et al Int J Mol Sci 2014; 15: 774. This work is licensed under a Creative Commons Attribution 3.0 Unported License.]

Drugs loaded into electrospun fiber through blending often exhibit burst release due to proximity of the drugs to the surface of the fiber and penetration of the medium into the matrix. This may not be appropriate for some medical treatment and it is also not possible to control the release rate due to the even distribution of drugs throughout the fibers. Core-shell fibers with the active compounds loaded at the core have the advantage of having a slower release rate due to the presence of an additional barrier layer between the drugs and the fiber surface. Repanas et al (2015) compared the released rate of acetylsalicylic in polycaprolactone fibers from blending and core-shell electrospinning (with acetylsalicylic at the core). Given the similar physical and structural profiles of both fibers in terms of fiber diameter, porosity and pore size, any differences in the drug release profile may be attributed to the differences in drug dispersion within the fibers. While both exhibits an initial burst release, the blended electrospun fibers released almost 60% of its load during the initial 8 hours while the core-shell fibers only released 34% over the same time. The initial burst release from core-shell fibers may be due to migration of some acetylsalicylic to the shell surface at the spinneret tip as the same solvent was used for mixing acetylsalicylic and dissolving polycaprolactone. At day 45, the cumulative drug released from core-shell fibers was 85% and the blended fibers were more than 97%. The rate of release may be controlled by varying the thickness of the shell material. Yan et al (2014) varied the feed ratio between the inner polyvinyl alcohol solution and the outer chitosan solution and showed the reduction in the release of doxorubicin (DOX) from the core when the feed ratio of chitosan solution increases. Chitosan was selectively crosslinked by glutaraldehyde vapor to reduce DOX release rate.

Coaxial Nozzle for electrospinning core-shell fibers from ramé-hart instrument [Sponsored Info]
Although human ovary cancer cells (SKOV3) seeded on the drug loaded scaffold showed good attachment, proliferation and spreading initially, they start to deteriorate after 8 days which is due to the time dependent drug release from the fibers. Ye et al (2020) investigated the use of core-shell electrospun fibers for delivery of the drug, emodin. Emodin has been shown to be effective against Methicillin-resistant Staphylococcus aureus (MRSA). In its unencapsulated form, emodin is crystalline and hydrophobic which limits its usage. When emodin was blended into poly(vinylpyrrolidone) (PVP) solution and electrospun in a core-shell fiber structure, it existed in an amorphous form. The core of the fiber was made of hydrophilic PVP and emodin while the sheath was made of hygroscopic cellulose acetate (CA). In vitro drug release test showed that the dissolution rate of emodin from the nanofiber membranes was significantly higher than that of raw emodin. At 156 h, more than 99% of emodin has been released from the electrospun membrane but only 31% was dissolved from raw emodin. The emodin release profile showed a burst release of 49% in the first 0.5 h followed by sustained release over the next 6 days. The rapid release in the first 0.5 h may be due to higher concentration of emodin at the core-shell interface between the PVP and CA which migrates quickly through the CA matrix. Subsequent sustained release comes from emodin trapped in the PVP matrix. Tests on the efficacy of the emodin loaded membrane with MRSA showed clear inhibition for 24 h and up to 9 days without reduction in the inhibition zone size. Varying feed rate of either inner material [Joung et al 2011] or outer material has also been successfully demonstrated for drug release.

Although designed to retard drug release rate, core-shell fibers may still demonstrate faster drug release than from blended system given the right processing conditions. Zhao et al (2014) showed that the release of Vit C from a core polyethylene glycol carrier and a PCL shell was much faster than when Vit C was blended with PCL matrix. They attributed this observation to the "edge effect" where the exposed edge of the core-shell fibers led to a continuous and rapid release of Vit C.

The concept of core-shell fibers for controlled drug release is not restricted to just a single core. Chang et al (2020) constructed a dual-core fibers for the purpose of drug delivery. For this setup, there were two core chambers surrounded by a sheath wall. The resultant fiber contained two separate cores encapsulated within a single sheath material.


Designs of the complex spinneret for implementing trifluid electrospinning: (a) a digital image showing a full view of the spinneret; (b) front view; (c) side view; and (d) a diagram about the organization of a structural outlet from three inlets [Chang et al 2020].

Eudragits of different molecular weight and response to pH were used as the sheath and core materials. An active ingredient, paracetamol, was added to Eudragits in the sheath and cores of the fiber. The resultant electrospun fibers have an average diameter of 660 nm. From their SEM and TEM images, it is possible to see two distinct cores within a single sheath material.


Morphologies and inner structural characteristics of the resultant sheath-separate-core nanofibers: (a) SEM images of the cross-sections, and (b) TEM image of the inner complex nanostructures [Chang et al 2020].

Drug release tests were carried out at three dissolution media with pH values of 2.0, 6.0 and 7.4. The paracetamol was found to release in three different stages depending on the pH and duration. Such release may coincide with the location of the drug release agent. Base on the release profile with respect to pH and time, the release at the three targeted places, stomach, small intestines and colon were 24.4%, 46.7%, and 28.6%, respectively


Trapping agent

Instead of directly loading the drug into the nanofiber matrix, a drug carrier that is loaded into the nanofiber matrix may be used to influence the rate of drug release. The drug carrier may act as an additional barrier or exhibits stronger adhesion for the drugs. Hu et al (2013) used mesoporous silica nanoparticles (MSNs) as drug carrier or delivery vehicle for Ibuprofen. MSNs with Ibuprofen loaded were then blended for electrospinning to form poly-L-lactide fibers. The use of MSNs carrier significantly reduces the initial burst release rate of Ibuprofen compared to Ibuprofen loaded directly into the polymer matrix from 46% down to 6% within the first 12 h [Hu et al 2013]. Similarly, laponite, a synthetic clay material, has also been used to encapsulate drug (amoxicillin) for mixing with a polymer solution (polylactic-co-glycolic acid) for electrospinning. A longer sustained drug release was observed for drug-loaded laponite in polymer matrix compared to drug in polymer matrix [Wang et al 2012].


Comparison of release profile of nifedipine encapsulated by Eudragit L-100 and Eudragit L-100 + PE-b-PEO [Costa et al International Journal of Polymer Science 2015; 2015: 902365. This work is licensed under a Creative Commons Attribution 3.0 Unported License.]

Another form of drug carrier is micelle-encapsulation. Yang et al (2014) used amphiphilic mono-methoxy poly(ethylene glycol)-blockpoly(e-caprolactone) (mPEG-PCL) copolymers to encapsulate Circumin and form micelles. The micelles were mixed into polyvinyl alcohol (PVA) solution and electrospun to form fibers. A check on the release rate showed significantly slower drug release from the nanofiber with circumin-loaded micelle but faster release with circumin-loaded micelle alone. Similarly, Costa et al (2015) used block copolymers of poly(ethylene)-b-poly(ethylene oxide) (PE-b-PEO) to retard the release of nifedipine in electrospun Eudragit L-100 fibers. Their study showed that with the addition PE-b-PEO, the release rate of nifedipine in electrospun Eudragit L-100 fibers is significantly slower than nifedipine in electrospun Eudragit L-100 fibers. PE-b-PEO in Eudragit L-100 forms micelle that traps nifedipine in its core. This combination was shown to be capable of prolonging the drug release when the loaded nanofibers are placed in a high pH environment.


Superhydrophobic membrane

A normally hydrophobic material when electrospun to form a fibrous membrane is known to exhibit greater water contact angle than its film form. Yohe et al (2012a) demonstrated the potential use of superhydrophobic characteristic of electrospun membrane to control drug release. The concept works by controlling the amount of wetting of the membrane by water. For a superhydrophobic material, wetting takes place gradually and as the porous membrane gets wetted through its thickness, drugs loaded into the fibers will be released upon contacting water. Therefore, a more hydrophobic material will show a slower release rate. Electrospun polycaprolactone (PCL) when doped with poly(glycerol monostearate-co-ε-caprolactone) (PGC-C18) has been shown to increases its water contact angle. Drug release rate from electrospun PCL doped with higher concentration of PGC-C18 demonstrated a corresponding reduction in release rate [Yohe et al 2012a, Yohe et al 2012b]. Electrospun PCL membrane that is completely wetted showed a burst release profile where all the drugs are unloaded within a day. With PCL doped with PGC-C18, the release rate was extended to 17 days. However, when wetting of the membrane is kept slow and allowed to proceed naturally, the release duration of PCL membrane and the PCL membrane doped with PGC-C18 was 14 days and 70 days respectively [Yohe et al 2012b].


Environmental Condition

The environment which the drug loaded electrospun nanofibers are used often exerts a profound effect on the rate of drug release. For fast release carrier, material with high water solubility is used for the construction of the drug loaded nanofibrous membrane. Similarly selection of the membrane material will depends on the usage environment such as temperature, pH or light response. Solubility of polyvinyl alcohol (PVA) in water is known to be influenced by the water temperature. The use of PVA either alone or blended with a second polymer may be used to control the rate at which encapsulated drugs are released in accordance to the expected environmental temperature [Azarbayjani et al 2010]. The pH of the media is also a common stimulus for drug release. Biodegradable pH-sensitive polymers containing ortho ester groups such as D,L-lactide have been shown to increase the drug release rate in acidic media [Qi et al 2008].


Nanofibrous Assembly

Research on controlling drug release from electrospun fibers has largely been on the materials and component level. Another way to control drug release is from an assembly level. Lu et al (2011) used a sandwich structure to control the release of zoledronic acid. Polyethylene oxide (PEO) was used as the carrier polymer for zoledronic acid. The electrospun PEO containing the drug was sandwiched between two layers of electrospun poly(L-lactide) (PLA). Their study showed that the initial release of drug can be controlled by varying the thickness of the encapsulating nanofibrous membrane.

Another way of controlling drug release is to use coating over the electrospun drug carrier. Kiaee et al (2016) used electrospun polyvinyl alcohol as the carrier for tetracycline. An overlay of polycaprolactone fibers were electrospun over the PVA carrier. PCL was selected due to its hydrophobic characteristics. Finally, the fibrous sandwich was encapsulated within chitosan by dipping in its solution. The drug release profile was investigated in sodium acetate buffer of pH 5.5. With the chitosan coating, an initial burst release of up to 69% of the drugs within the first 5 hours were recorded followed by sustained release for the next 168 hours. Without the chitosan coating, PVA loaded tetracycline and PCL fibers released all the drugs within 20 hours.


Structural Composites

Fibers can be used as load bearing structure and the incorporation of drugs into it may adversely change its mechanical properties. To counter this effect, Ionescu et al (2010) created a composite comprising of microspheres and nanofibers with microspheres for drug release and nanofibers for load bearing. The composite is constructed by simultaneously electrospinning fibers and electrospraying microsphere in a carrier polymer solution on either side of a rotating drum collector. This setup allows the microspheres to be entrapped within the electrospun fibers. Mechanical tests showed no changes in the stiffness of the electrospun membrane at any microsphere density [Ionescu et al 2010]. Given that there is a possibility that the microspheres may slip out of the fiber membrane, an alternative is to mix electrospun fibers with and without drug loaded using the same setup. This way, there is no chance of drug loaded fibers from migrating while retaining mechanical strength.



Published date: 02 December 2014
Last updated: 11 July 2023

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